tbuckley/cabot-search huggingface dataset:
Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors
Authors: Rachel E Sanborn, Michael J Pishvaian, Margaret K Callahan, Amy Weise, Branimir I Sikic, Osama Rahma, Daniel C Cho, Naiyer A Rizvi, Mario Sznol, Jose Lutzky, Julie E Bauman, Rhonda L Bitting, Alexander Starodub, Antonio Jimeno, David A Reardon, Thomas Kaley, Fabio Iwamoto, Joachim M Baehring, Deepa S Subramaniam, Jeanny B Aragon-Ching, Thomas R Hawthorne, Tracey Rawls, Michael Yellin, Tibor Keler
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naïve, refractory solid tumors. Methods Phase 1 evaluated the safety of varlilumab (0.1–10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures. Results 175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%). Conclusion Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian cancer where the changes were associated with better clinical outcomes. Trial registration number NCT02335918 .
Postmenopausal osteoporosis.
Authors: R Eliakim, A Foldes, J Menczel
Journal: BMJ (1982)

The objective of this study was to determine the safety and efficacy of long-term minodronate treatment in women with postmenopausal osteoporosis based on reanalysis of a phase III 2-year clinical trial with a 1-year extension.Women aged 55-80 years old with fragility fractures were enrolled and randomized to take 1 mg minodronate or placebo once a day in the original 2-year study.The subjects who completed the 2-year study were invited to participate in an additional 1-year extension in which all subjects were to receive minodronate.Finally, a total 380 subjects completed the extension study (186 from the placebo group and 194 from the minodronate group).Fracture results observed in the extension study were consistent with those observed in the first 2 years in minodronate group.In contrast, the placebo/minodronate group showed a decreased incidence of new vertebral fractures during year 3 compared to that in year 2. In the patients who received minodronate in the original 2-year study, lumbar bone mineral density (BMD) increased consistently during year 3 and bone turnover markers decreased within the first 6 months and remained constant thereafter over 3 years.Similar positive effects of minodronate on BMD and bone turnover markers occurred when therapy was initiated in the placebo/minodronate group.No new safety concerns observed during the extension period compared to the safety observations made during the 2-year study.It was concluded that daily administration of 1 mg oral minodronate is safe and well tolerated, and that the efficacy of this dose in reducing vertebral fracture risk in postmenopausal women over 2 years is sustained with continuing treatment.
Postmenopausal Osteoporosis
Authors: Angela M Cheung, Alexandra Papaioannou, Suzanne Morin
Journal: New England Journal of Medicine (2016)

Our ultimate goal is to make donor-candidate education and acceptance more empiric and defensible.Our study provides a framework for donor evaluation that is centered on the simultaneous consideration of many clinical factors relevant to the risk of end-stage renal disease, but its application requires insight and sensitivity to nuance on the part of the clinician.Suggested framing is described in detail in the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for clinical practice. 5 We see our work as a starting point and advocate strongly for continued efforts to improve the precision and generalizability of estimates of risk before and after donation.
Profiling of epigenetic marker regions in murine ILCs under homeostatic and inflammatory conditions
Authors: Michael Beckstette, Chia-Wen Lu, Susanne Herppich, Elia C. Diem, Anna Ntalli, Aaron Ochel, Friederike Kruse, Beate Pietzsch, Katrin Neumann, Jochen Huehn, Stefan Floess, Matthias Lochner
Journal: The Journal of Experimental Medicine (2022)

Epigenetic modifications such as DNA methylation play an essential role in imprinting specific transcriptional patterns in cells. We performed genome-wide DNA methylation profiling of murine lymph node–derived ILCs, which led to the identification of differentially methylated regions (DMRs) and the definition of epigenetic marker regions in ILCs. Marker regions were located in genes with a described function for ILCs, such as Tbx21, Gata3, or Il23r, but also in genes that have not been related to ILC biology. Methylation levels of the marker regions and expression of the associated genes were strongly correlated, indicating their functional relevance. Comparison with T helper cell methylomes revealed clear lineage differences, despite partial similarities in the methylation of specific ILC marker regions. IL-33–mediated challenge affected methylation of ILC2 epigenetic marker regions in the liver, while remaining relatively stable in the lung. In our study, we identified a set of epigenetic markers that can serve as a tool to study phenotypic and functional properties of ILCs.
The landscape in the gut microbiome of long-lived families reveals new insights on longevity and aging – relevant neural and immune function
Authors: Jingjing Wang, Jinlong Qie, Danrong Zhu, Xuemei Zhang, Qingqing Zhang, Yuyu Xu, Yipeng Wang, Kai Mi, Yang Pei, Yang Liu, Guozhong Ji, Xingyin Liu
Journal: Gut Microbes (2022)

Human longevity has a strong familial and genetic component. Dynamic characteristics of the gut microbiome during aging associated with longevity, neural, and immune function remained unknown. Here, we aim to reveal the synergistic changes in gut microbiome associated with decline in neural and immune system with aging and further obtain insights into the establishment of microbiome homeostasis that can benefit human longevity. Based on 16S rRNA and metagenomics sequencing data for 32 longevity families including three generations, centenarians, elderly, and young groups, we found centenarians showed increased diversity of gut microbiota, severely damaged connection among bacteria, depleted in microbial-associated essential amino acid function, and increased abundance of anti-inflammatory bacteria in comparison to young and elderly groups. Some potential probiotic species, such as Desulfovibrio piger, Gordonibacter pamelaeae, Odoribacter splanchnicus, and Ruminococcaceae bacterium D5 were enriched with aging, which might possibly support health maintenance. The level of Amyloid-β (Aβ) and brain-derived neurotrophic factor (BDNF) related to neural function showed increased and decreased with aging, respectively. The elevated level of inflammatory factors was observed in centenarians compared with young and elderly groups. The enriched Bacteroides fragilis in centenarians might promote longevity through up-regulating anti-inflammatory factor IL-10 expression to mediate the critical balance between health and disease. Impressively, the associated analysis for gut microbiota with the level of Aβ, BDNF, and inflammatory factors suggests Bifidobacterium pseudocatenulatum could be a particularly beneficial bacteria in the improvement of impaired neural and immune function. Our results provide a rationale for targeting the gut microbiome in future clinical applications of aging-related diseases and extending life span.Abbreviations: 16S rRNA: 16S ribosomal RNA; MAGs: Metagenome-assembled genomes; ASVs: Amplicon sequence variants; DNA: Deoxyribonucleic acid; FDR: False discovery rate: KEGG: Kyoto Encyclopedia of Genes and Genomes; PCoA: Principal coordinates analysis; PCR: Polymerase chain reaction; PICRUSt: Phylogenetic Investigation of Communities by Reconstruction of Unobserved States; Aβ: Amyloid-β (Aβ); BDNF: Brain-derived neurotrophic factor
A single cell survey of the microbial impacts on the mouse small intestinal epithelium
Authors: Derek K.L. Tsang, Ryan J. Wang, Oliver De Sa, Arshad Ayyaz, Elisabeth G. Foerster, Giuliano Bayer, Shawn Goyal, Daniel Trcka, Bibaswan Ghoshal, Jeffrey L. Wrana, Stephen E. Girardin, Dana J. Philpott
Journal: Gut Microbes (2022)

The small intestinal epithelial barrier inputs signals from the gut microbiota in order to balance physiological inflammation and tolerance, and to promote homeostasis. Understanding the dynamic relationship between microbes and intestinal epithelial cells has been a challenge given the cellular heterogeneity associated with the epithelium and the inherent difficulty of isolating and identifying individual cell types. Here, we used single-cell RNA sequencing of small intestinal epithelial cells from germ-free and specific pathogen-free mice to study microbe-epithelium crosstalk at the single-cell resolution. The presence of microbiota did not impact overall cellular composition of the epithelium, except for an increase in Paneth cell numbers. Contrary to expectations, pattern recognition receptors and their adaptors were not induced by the microbiota but showed concentrated expression in a small proportion of epithelial cell subsets. The presence of the microbiota induced the expression of host defense- and glycosylation-associated genes in distinct epithelial cell compartments. Moreover, the microbiota altered the metabolic gene expression profile of epithelial cells, consequently inducing mTOR signaling thereby suggesting microbe-derived metabolites directly activate and regulate mTOR signaling. Altogether, these findings present a resource of the homeostatic transcriptional and cellular impact of the microbiota on the small intestinal epithelium.
Approaches to discern if microbiome associations reflect causation in metabolic and immune disorders
Authors: Marijana Basic, Dominique Dardevet, Peter Michael Abuja, Silvia Bolsega, Stéphanie Bornes, Robert Caesar, Francesco Maria Calabrese, Massimo Collino, Maria De Angelis, Philippe Gérard, Miguel Gueimonde, François Leulier, Eva Untersmayr, Evelien Van Rymenant, Paul De Vos, Isabelle Savary-Auzeloux
Journal: Gut Microbes (2022)

Our understanding of microorganisms residing within our gut and their roles in the host metabolism and immunity advanced greatly over the past 20 years. Currently, microbiome studies are shifting from association and correlation studies to studies demonstrating causality of identified microbiome signatures and identification of molecular mechanisms underlying these interactions. This transformation is crucial for the efficient translation into clinical application and development of targeted strategies to beneficially modulate the intestinal microbiota. As mechanistic studies are still quite challenging to perform in humans, the causal role of microbiota is frequently evaluated in animal models that need to be appropriately selected. Here, we provide a comprehensive overview on approaches that can be applied in addressing causality of host-microbe interactions in five major animal model organisms (Caenorhabditis elegans, Drosophila melanogaster, zebrafish, rodents, and pigs). We particularly focused on discussing methods available for studying the causality ranging from the usage of gut microbiota transfer, diverse models of metabolic and immune perturbations involving nutritional and chemical factors, gene modifications and surgically induced models, metabolite profiling up to culture-based approached. Furthermore, we addressed the impact of the gut morphology, physiology as well as diet on the microbiota composition in various models and resulting species specificities. Finally, we conclude this review with the discussion on models that can be applied to study the causal role of the gut microbiota in the context of metabolic syndrome and host immunity. We hope this review will facilitate important considerations for appropriate animal model selection.
A Novel Biopsy Capsule Robot Based on High-Speed Cutting Tissue
Authors: Zhibin Song, Wenjie Zhang, Wenhui Zhang, Dario Paolo
Journal: Cyborg and Bionic Systems (2022)

The capsule robot (CR) is a promising endoscopic method in gastrointestinal diagnosis because of its low discomfort to users. Most CRs are used to acquire image information only and lack the ability to collect samples. Although some biopsy capsule robots (BCRs) have been developed, it remains challenging to acquire the intestinal tissue while avoiding tearing and adhesion due to the flexibility of colonic tissue. In this study, we develop a BCR with a novel sampling strategy in which soft tissue is scratched with sharp blades rotating at high speed to avoid tissue tearing. In the BCR design, a spiral spring with prestored energy is used to release high energy within a short period of time, which is difficult for a motor or magnet to perform within a small capacity installation space. The energy of the tightened spiral spring is transmitted to drive sharp blades to rotate quickly via a designed gear mechanism. To guarantee reliable sampling, a Bowden cable is used to transmit the user’s manipulation to trigger the rotation of the blades, and the triggering force transmitted by the cable can be monitored in real time by a force sensor installed at the manipulating end. A prototype of the proposed BCR is designed and fabricated, and its performance is tested through in vitro experiments. The results show that the proposed BCR is effective and the size of its acquired samples satisfies clinical requirements.
Leptospirosis in man, British Isles, 1982.
Journal: BMJ (1983)

During 1982, 61 cases of leptospirosis were confirmed by the PHLS Leptospira Reference Unit, a number comparable with the average of 58 for the preceding three year period.'Four of the patients died.Seven infections were thought to have been contracted abroad-two in West Germany, and one each in Brunei, Jamaica, Seychelles, south east Asia, and Spain.Of the remaining 54 cases, 16 were from the Republic of Ireland, three ages were recorded among the working population and only one under 15 years of age.
Monkeypox from Congo 1970 to Europe 2022; is there a difference?
Authors: Abdulrhman Khaity, Hanan Hasan, Khaled Albakri, Hanaa Elsayed, Hussien Ahmed H Abdelgawad, Fahadul Islam, Manish Dhawan, Hazem S. Ghaith, Talha Bin Emran
Journal: International Journal of Surgery (2022)
Dermatoscopic features differentiating among port wine stain, arteriovenous malformation, and capillary malformation-arteriovenous malformation syndrome: to detect potential fast-flow vascular malformations at an early stage
Authors: Yi Sun, Lixin Su, Yunjie Zhang, Zhenfeng Wang, Shijie Chen, Hao Gu, Xiaojie Yue, Xiong Zhao, Xitao Yang, Deming Wang, Xindong Fan, Ren Cai
Journal: Journal of the American Academy of Dermatology (2022)
Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease
Authors: Anna R. Hemnes, Jane A. Leopold, Milena K. Radeva, Gerald J. Beck, Aiden Abidov, Micheala A. Aldred, John Barnard, Erika B. Rosenzweig, Barry A. Borlaug, Wendy K. Chung, Suzy A.A. Comhair, Ankit A. Desai, Hilary M. Dubrock, Serpil C. Erzurum, J. Emanuel Finet, Robert P. Frantz, Joe G.N. Garcia, Mark W. Geraci, Michael P. Gray, Gabriele Grunig, Paul M. Hassoun, Kristin B. Highland, Nicholas S. Hill, Bo Hu, Deborah H. Kwon, Miriam S. Jacob, Christine L. Jellis, A. Brett Larive, Jason K. Lempel, Bradley A. Maron, Stephen C. Mathai, Kevin McCarthy, Reena Mehra, Rawan Nawabit, John H. Newman, Mitchell A. Olman, Margaret M. Park, Jose A. Ramos, Rahul D. Renapurkar, Franz P. Rischard, Susan G. Sherer, W.H. Wilson Tang, James D. Thomas, Rebecca R. Vanderpool, Aaron B. Waxman, Jennifer D. Wilcox, Jason X.-J. Yuan, Evelyn M. Horn
Journal: Journal of the American College of Cardiology (2022)
Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function
Authors: Daniel B. Rosoff, Andrew S. Bell, Jeesun Jung, Josephin Wagner, Lucas A. Mavromatis, Falk W. Lohoff
Journal: Journal of the American College of Cardiology (2022)

Lipid-lowering therapy with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition are effective strategies in reducing cardiovascular disease risk; however, concerns remain about potential long-term adverse neurocognitive effects. This genetics-based study aimed to evaluate the relationships of long-term PCSK9 inhibition and statin use on neurocognitive outcomes. We extracted single-nucleotide polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and PCSK9 from predominantly European ancestry-based genome-wide association studies summary-level statistics of low-density lipoprotein cholesterol and performed drug-target Mendelian randomization, proxying the potential neurocognitive impact of drug-based PCSK9 and HMGCR inhibition using a range of outcomes to capture the complex facets of cognition and dementia. Using data from a combined sample of ∼740,000 participants, we observed a neutral cognitive profile related to genetic PCSK9 inhibition, with no significant effects on cognitive performance, memory performance, or cortical surface area. Conversely, we observed several adverse associations for HMGCR inhibition with lowered cognitive performance (beta: –0.082; 95% CI: –0.16 to –0.0080; P = 0.03), reaction time (beta = 0.00064; 95% CI: 0.00030-0.00098; P = 0.0002), and cortical surface area (beta = –0.18; 95% CI: –0.35 to –0.014; P = 0.03). Neither PCSK9 nor HMGCR inhibition impacted biomarkers of Alzheimer’s disease progression or Lewy body dementia risk. Consistency of findings across Mendelian randomization methods accommodating different assumptions about genetic pleiotropy strengthens causal inference. Using a wide range of cognitive function and dementia endpoints, we failed to find genetic evidence of an adverse PCSK9-related impact, suggesting a neutral cognitive profile. In contrast, we observed adverse neurocognitive effects related to HMGCR inhibition, which may well be outweighed by the cardiovascular benefits of statin use, but nonetheless may warrant pharmacovigilance.
Dissecting the histological features of lupus nephritis highlights new common patterns of injury in class III/IV
Authors: Maddalena Maria Bolognesi, Giulia Capitoli, Stefania Galimberti, Giorgio Cattoretti, Ingeborg Bajema, Jan A Bruijn, H Terence Cook, Laure-Helene Noel, Fabio Pagni, Franco Ferrario, Maria Wester Trejo, Vincenzo L'Imperio
Journal: Annals of the Rheumatic Diseases (2022)

The International Society of Nephrology/Renal Pathology Society classification is the gold standard for the characterisation of lupus nephritis (LN) on renal biopsy, with therapeutic repercussions. Its recent revision simplified the current class subdivisions, eliminating the S/G forms of class IV, although data on a possible pathogenetic/clinical value of this subdivision are still contradictory.353 renal biopsies from Belimumab International Study in LN were assessed through central pathology review. Univariate logistic models and a decision tree were performed on 314 adequate biopsies to evaluate the impact of histological features on focal/diffuse classes. Removing class I/II (n=6) and 'pure' class V (n=34), principal component analysis (PCA) and heatmap were used to explore similarities among III, IVS and IVG biopsies either incorporating or not the mixed classes (+V, n=274). Finally, a method aimed at partitioning the cases into k clusters based on their similarity (KMeans), was used to study features from the cohort of 'pure' class III/IVS/IVG cases (n=214) to determine alternative subdivisions based on phenotypic data.Segmental endocapillary hypercellularity (EH) was prevalent in class III, global EH, wire loops, hyaline thrombi and double contours were hallmarks of class IVG, with IVS cases showing intermediate characteristics. Heatmap and PCA confirmed the segregation of these features among classes, showing better segregation for focal/diffuse LN as compared with the mixed classes (+V). KMeans revealed the presence of two main clusters, membranoproliferative-like (n=83) or vasculitis-like (n=131).This study reveals new phenotypic forms of LN surpassing the traditional classes as determined by the current classification. Future validation and confirmation are required to confirm these findings.
Prevalence and Prognostic Implications of Discordant Grading and Flow-Gradient Patterns in Moderate Aortic Stenosis
Authors: Jan Stassen, See Hooi Ewe, Gurpreet K. Singh, Steele C. Butcher, Kensuke Hirasawa, Mohammed R. Amanullah, Stephan M. Pio, Kenny Y.K. Sin, Zee P. Ding, Ching-Hui Sia, Nicholas W.S. Chew, William K.F. Kong, Kian Keong Poh, Martin B. Leon, Philippe Pibarot, Victoria Delgado, Nina Ajmone Marsan, Jeroen J. Bax
Journal: Journal of the American College of Cardiology (2022)
Management of Patients With Severe Mitral Annular Calcification
Authors: Omar Chehab, Ross Roberts-Thomson, Antonio Bivona, Harminder Gill, Tiffany Patterson, Amit Pursnani, Karine Grigoryan, Bernardo Vargas, Ujala Bokhary, Christopher Blauth, Gianluca Lucchese, Vinayak Bapat, Mayra Guerrero, Simon Redwood, Bernard Prendergast, Ronak Rajani
Journal: Journal of the American College of Cardiology (2022)
Diphtheroid Endocarditis After Insertion of a Prosthetic Heart Valve
Authors: Warren D. Johnson
Journal: JAMA (1968)

In two cases of diphtheroid endocarditis after insertion of Starr-Edwards ball-valve prostheses, the source of infection was most likely related to the cardiopulmonary bypass procedure. Although diphtheroids are common contaminants in blood cultures, these organisms are an important cause of bacterial endocarditis especially in patients who have had open-heart surgery.
Profiling of syngeneic mouse HCC tumor models as a framework to understand anti–PD‐1 sensitive tumor microenvironments
Authors: Daniel J. Zabransky, Ludmila Danilova, James M. Leatherman, Tamara Y. Lopez‐Vidal, Jessica Sanchez, Soren Charmsaz, Nicole E. Gross, Sarah Shin, Xuan Yuan, Alexei Hernandez, Hongqui Yang, Stephanie Xavier, Daniel Shu, Ali Saeed, Kabeer Munjal, Zeal Kamdar, Luciane T. Kagohara, Elizabeth M. Jaffee, Mark Yarchoan, Won Jin Ho
Journal: Hepatology (2022)

The treatment of hepatocellular carcinoma (HCC) has been transformed by the use of immune checkpoint inhibitors. However, most patients with HCC do not benefit from treatment with immunotherapy. There is an urgent need to understand the mechanisms that underlie response or resistance to immunotherapy for patients with HCC. The use of syngeneic mouse models that closely recapitulate the heterogeneity of human HCC will provide opportunities to examine the complex interactions between cancer cells and nonmalignant cells in the tumor microenvironment.